Hormone replacement therapy (menopause)

Hormone replacement therapy (HRT) is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women. It is based on the idea that the treatment may prevent discomfort caused by diminished circulating oestrogen and progesterone hormones, or in the case of the surgically or prematurely menopausal, that it may prolong life and may reduce incidence of dementia.^[1] It involves the use of one or more of a group of medications designed to artificially boost hormone levels. The main types of hormones involved are oestrogens, progesterone or progestins, and sometimes testosterone. It often referred to as "treatment" rather than therapy.

Overview

HRT is available in various forms. It generally provides low dosages of one or more oestrogens, and often also provides either progesterone or a chemical analogues, called a progestin. Testosterone may also be included. In women who have had a hysterectomy, an oestrogen compound is usually given without any progesterone, a therapy referred to as "unopposed estrogen therapy". HRT may be delivered to the body via patches, tablets, creams, troches, IUDs, vaginal rings, gels or, more rarely, by injection. For example, vaginally administered estrogens include those given by intravaginal tablets, creams and rings, and can have more effect on atrophic vaginitis with less systemic effects.^[2]

Dosage is often varied cyclically, with estrogens taken daily and progesterone or progestins taken for about two weeks every month or two; a method called "sequentially combined HRT" or scHRT. An alternate method, a constant dosage with both types of hormones taken daily, is called "continuous combined HRT" or ccHRT, and is a more recent innovation. Sometimes an androgen, generally testosterone, is added to treat diminished libido. It may also treat reduced energy and help reduce osteoporosis after menopause.

HRT is often given as a short-term relief (often one or two years, usually less than five) from menopausal symptoms (hot flashes, irregular menstruation, fat redistribution etc.). Younger women with premature ovarian failure or surgical menopause may use hormone replacement therapy for many years, until the age that natural menopause would be expected to occur.

Attitudes towards HRT changed in 2002 following the announcement by the Women's Health Initiative of the National Institutes of Health that those receiving the treatment (Prempro) in the main part of their study had a larger incidence of breast cancer, heart attacks and strokes.^[3] The WHI findings were reconfirmed in a larger national study done in the UK, known as The Million Women Study. As a result of these findings, the number of women taking hormone treatment dropped precipitously.^[4] As a result of these findings, the Women's Health Initiative recommended that women with normal rather than surgical menopause should take the lowest feasible dose of HRT for the shortest possible time to avoid these risks.^[3]

Risks and benefits

Proprietary mixtures of conjugated equine estrogens (CEE, Premarin is one such CEE), estrogens derived from the urine of pregnant mares, have been a common prescribed form of HRT, as well as progestins. As the most common and longest-prescribed type of HRT, the majority of studies of HRT involve CEE. More recent forms of drug delivery have been researched, including suppositories, subdermal implants, skin patches and gels rather than pills or injections, which allow more local effect, lower doses, fewer side effects and a constant rather than cyclical level of hormones within the blood.^[5] Comparisons between a pill and transdermal patch suggests that when estrogens are taken orally the risks of thrombophlebitis and pulmonary embolism are increased, an effect which is not seen in with transdermal administration (this effect refers only to patches that contain estradiol for hormone replacement, and has no bearing on the patches used for birth control, which contain ethinyl estradiol). Transdermal drugs enter the bloodstream directly and unlike oral estrogens are not modified by the liver before being absorbed (modification by the liver is believed to be the reason for the increased risks).^[6] Once considered protective of the cardiovascular system, the large-scale, randomized, placebo controlled studies in the Women's Health Initiative found that conventional hormone therapy with CEE actually increased the risk of heart disease, strokes, emboli and breast cancer while offering only mild protection against osteoporosis and colorectal cancer.^[7] Unopposed estrogen (the supplementation of endogenous estrogens without a progestagen) can also result in endometrial hyperplasia, a precursor to endometrial cancer. The extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of this type of cancer.^[8]

HRT may also be effective at reversing the effects of aging on muscle ^[9] and/or promoting reverse cholesterol transport (RCT) via the induction of cholesterol ABC transporters.^[10]

Women have also pursued alternative interventions which do not involve estrogen supplementation. Due to the risks and potential problems of progestins and equine estrogens, a number of alternative therapies have been presented, including lifestyle changes and phytoestrogens (plants and food supplements believed to alleviate the symptoms of menopause due to estrogen-like compounds). However, systemic reviews of the research on phytoestrogens demonstrated that these compounds are not effective.^[11] Bioidentical hormone replacement therapy has also been inaccurately promoted as a panacea and an alternative to conventional HRT, but bioidentical hormones are derived from the same sources as nonbioidentical molecules, have been used in FDA-approved drugs for many years, lack a research base demonstrating their risks or benefits, are expected to have the same risks and benefits as conventional HRT, and frequently associated with the expensive, unnecessary and potentially dangerous practice of compounding .^[12]

According to a 2007 presentation at an American Academy of Neurology meeting,^[13] hormone therapy taken soon after menopause may help protect against dementia, even though it raises the risk of mental decline in women who do not take the drugs until they are older. Dementia risk was 1% in women who started HRT early, and 1.7% in women who didn't, (e.g. women who didn't take it seem to have had—on average—a 70% higher relative risk of dementia). This is consistent with research that hormone therapy improves executive and attention processes in postmenopausal women.^[14] It is also supported by research upon monkeys that were given ovariectomies to imitate the effect of menopause and then estrogen therapies. This showed replacement treated compared to nontreated monkeys had long term improved prefrontal cortex executive abilities on the Wisconsin card sort task.^[15]

Another recent randomized controlled trial found HRT may actually prevent the development of heart disease and reduce the incidence of heart attack in women between 50 and 59, but not for older women. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus improving both "good" and "bad" cholesterol concentrations in the blood (which would have a protective effect). Followup studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.^[16]

A recent large well-designed randomized controlled trial recently showed that increased breast cancer risk applies only to those women who take progesterone analogues (as was done in the WHI) but not to those taking progesterone itself ^[17]

Results of the WHI hormone replacement therapy studies

Clinical medical practice changed rapidly and dramatically with the results of the two parallel WHI studies of postmenopausal HRT. Prior studies were much smaller, and many were studies of women who were electively taking hormones. This self-selected group tended to be composed of women who were more health-conscious, which was a possible factor to explain why these women tended to be healthier than the average. The WHI studies were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women. The WHI estrogen-plus-progestin trial and estrogen-alone trial were both halted early (in July 2002 and February 2004 respectively) because preliminary study results indicated that the health risks of the conjugated equine estrogen and progestin exceeded benefits.

The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.^[18] It followed over 16 000 women for an average of 5.2 years, half of which taking a placebo, the other half taking PremPro, a combination of the progestin medroxyprogesterone acetate and conjugated equine estrogens. The study found statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia." [1] The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with PremPro, the specific proprietary combination of conjugated equine estrogen and progestin studied.

The increase in risks of coronary heart disease in the PremPro arm of the study varied according to age and years since the onset of menopause. Women aged 50 to 59 using HRT showed a small trend towards lower risk of coronary heart disease,^[19] as did women who were within five years of the onset of menopause.^[20]

The adverse cardiovascular outcomes may only apply to oral dosing with the progestin and equine estrogens in Prempro, while other types of HRT such as topical estradiol and estriol may not produce the same risks. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased.^[6]

The WHI preliminary results in 2004 found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer^[19] and a 2006 update concluded that use of estrogen-only HRT for 7 years does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy.^[21] The results of the WHI estrogen-alone trial suggest that the progestin used in the WHI estrogen-plus-progestin trial increased the risk for breast cancer above that associated with estrogen alone.^[22]

After the increased clotting found in the first WHI results was reported in 2002, a large number of women who had been taking the proprietary mixtures of equine estrogens and progestins studied (Prempro) ceased filling their prescriptions. The number of Prempro prescriptions filled was abruptly cut almost in half. A number of women started taking alternatives to Prempro, such as bioidentical hormones.^[23] A sharp drop in breast cancer rates was observed following these changes, and held steady in subsequent years.^[24]

Bioidentical hormone replacement therapy

Main article: Bioidentical hormone replacement therapy

Bioidentical hormone replacement therapy refers to the use of hormones that are chemically identical to those produced in a woman's body, though they are also associated with the practices of pharmaceutical compounding and saliva testing to determine, and adjust a woman's hormone levels (the latter two practices are extremely controversial - compounding has not demonstrated any benefits and presents risks of uncertain dosing, potency and possible contamination; saliva testing is considered to have no merit due to the natural fluctuations in hormone levels and the lack of support for a specific dosage of hormones being ideal).^[12] Proponents also claim that BHRT can offer advantages beyond those typical of traditional HRT, though there is no evidence to support these claims. The United States Food and Drug Administration states that BHRT is expected to present the same risks and benefits of non-bioidentical HRT, but that traditional products have been researched to quantify these risks and benefits, and are produced by manufacturers with stringent purity and potency standards.^[25]

Contraindications

Absolute contraindications

• Undiagnosed vaginal bleeding
• Severe liver disease
• Pregnancy
• Coronary artery disease (CAD)
• Venous thrombosis
• Well-differentiated and early endometrial cancer (once treatment for the malignancy is complete, is no longer an absolute contraindication.) Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens.

Relative contraindications

• Migraine headaches
• Personal history of breast cancer
• Personal history of ovarian cancer
• History of uterine fibroids
• Atypical ductal hyperplasia of the breast
• Active gallbladder disease (cholangitis, cholecystitis)

Side effects

Common symptoms Headache Upset stomach, stomach cramps or bloating Diarrhea Appetite and weight changes Changes in sex drive or performance Nervousness Brown or black patches on the skin Acne Swelling of hands, feet, or lower legs due to fluid retention            Changes in menstrual flow Breast tenderness, enlargement, or discharge Sudden difficulty wearing contact lenses

Uncommon symptoms Double vision Severe abdominal pain Yellowing of skin or eyes Severe depression Unusual bleeding Loss of appetite Skin rash Laxitude Fever Dark-colored urine Light colored stool Chorea[26]

See also

Andropause Castration Estrogen European Menopause and Andropause Society Hormones Life extension

Male lactation North American Menopause Society Oophorectomy Osteoporosis Progesterone Prolactin

References

1. ^ Lynne T. Shuster, Deborah J. Rhodes, Bobbie S. Gostout, Brandon R. Grossardt, and Walter A. Rocca (2010). "Premature menopause or early menopause: long-term health consequences". Maturitas 65 (2): 161–6. doi:10.10.16/maturitas.2009.08.003. PMC 2815011. PMID 19733988. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2815011. 
2. ^ Estrogen (Vaginal Route) from Mayo Clinic / Thomson Healthcare Inc. Portions of this document last updated: Nov. 1, 2011
3. ^ ^{a b} Writing Group for the Women's Health Initiative Investigators (2002). "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial". JAMA 288 (3): 321–333. doi:10.1001/jama.288.3.321. PMID 12117397. http://jama.ama-assn.org/cgi/content/abstract/288/3/321. 
4. ^ Chlebowski, RT; Kuller LH; Prentice RL; Stefanick ML; Manson JE; Gass M; et al. (2009). "Breast cancer after use of estrogen plus progestin in postmenopausal women". NEJM 360 (6): 573–87. doi:10.1056/NEJMoa0807684. PMID 19196674. http://content.nejm.org/cgi/content/full/360/6/573. 
5. ^ Fraser IS, Mansour D (March 2006). "Delivery systems for hormone replacement therapy". Expert Opin Drug Deliv 3 (2): 191–204. doi:10.1517/17425247.3.2.191. PMID 16506947. 
6. ^ ^{a b} Scarabin PY, Oger E, Plu-Bureau G (2003). "Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk". Lancet 362 (9382): 428–32. doi:10.1016/S0140-6736(03)14066-4. PMID 12927428. 
7. ^ George, James L.; Colman, Robert W.; Goldhaber, Samuel Z.; Victor J. Marder (2006). Hemostasis and thrombosis: basic principles and clinical practice. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 1239. ISBN 0781749964. 
8. ^ Young, Robert; Arlan F., Jr Fuller; Fuller, Arlan F.; Michael V. Seiden (2004). Uterine cancer. Hamilton, Ont: B.C. Decker. ISBN 1-55009-163-8. 
9. ^ Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA (2009). "Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?". Bioessays 31 (6): 629–41. doi:10.1002/bies.200800138. PMID 19382224. 
10. ^ Darabi M, Rabbani M, Ani M, Zarean E, Panjehpour M, Movahedian A (2010). "Increased leukocyte ABCA1 gene expression in post-menopausal women on hormone replacement therapy.". Gynecol Endocrinol: 100901005659035. doi:10.3109/09513590.2010.507826. PMID 20807164. 
11. ^ Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J (2007). Lethaby, Anne. ed. "Phytoestrogens for vasomotor menopausal symptoms". Cochrane Database Syst Rev (4): CD001395. doi:10.1002/14651858.CD001395.pub3. PMID 17943751. 
12. ^ ^{a b} Boothby LA, Doering PL (August 2008). "Bioidentical hormone therapy: a panacea that lacks supportive evidence". Curr. Opin. Obstet. Gynecol. 20 (4): 400–7. doi:10.1097/GCO.0b013e3283081ae9. PMID 18660693. 
13. ^ Jeff Donn (2007-05-02). "Hormones may ward off dementia in women: Controversial treatment effective when taken soon after menopause". Associated Press. http://www.msnbc.msn.com/id/18440238. 
14. ^ Schmidt, R; Fazekas, F; Reinhart, B; Kapeller, P; Fazekas, G; Offenbacher, H; Eber, B; Schumacher, M et al. (1996). "Estrogen replacement therapy in older women: a neuropsychological and brain MRI study". J Am Geriatr Soc 44 (11): 1307–13. PMID 8909345. 
15. ^ Voytko, ML; Murray, R; Higgs, GJ. (2009). "Executive Function and Attention Are Preserved in Older Surgically Menopausal Monkeys Receiving Estrogen or Estrogen Plus Progesterone". Journal of Neuroscience 29 (33): 10362–10370. doi:10.1523/JNEUROSCI.1591-09.2009. PMC 2744632. PMID 19692611. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2744632. 
16. ^ Patti Neighmond (2006-02-13). "Hormones May Help Younger Women's Hearts". All Things Considered. http://www.npr.org/templates/story/story.php?storyId=5204360. 
17. ^ Fournier A, Berrino F, Clavel-Chapelon F. (2008). "Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study". Breast Cancer Res Treat 107 (1): 103–111. doi:10.1007/s10549-007-9523-x. PMC 2211383. PMID 17333341. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2211383. 
18. ^ Rossouw JE, Anderson GL, Prentice RL, et al. (2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397. 
19. ^ ^{a b} Anderson GL, Limacher M, Assaf AR, et al. (2004). "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial". JAMA 291 (14): 1701–12. doi:10.1001/jama.291.14.1701. PMID 15082697. http://jama.ama-assn.org/cgi/content/full/291/14/1701. 
20. ^ Manson, J.E.; Hsia, P.H.J., Johnson, K.C., Rossouw, J.E., Assaf, A.R., Lasser, N.L., Trevisan, M., Black, H.R., Heckbert, S.R., Detrano, R., Strickland, O.L., Wong, N.D., Crouse, J.R., Stein, E. & Cushman, M. (2003). "Estrogen plus Progestin and the Risk of Coronary Heart Disease". The New England Journal of Medicine 349 (6): 523–534. doi:10.1056/NEJMoa030808. PMID 12904517. 
21. ^ Stefanick ML, Anderson GL, Margolis KL, et al. (2006). "Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy". JAMA 295 (14): 1647–57. doi:10.1001/jama.295.14.1647. PMID 16609086. 
22. ^ Hulley SB, Grady D (2004). "The WHI estrogen-alone trial--do things look any better?". JAMA 291 (14): 1769–71. doi:10.1001/jama.291.14.1769. PMID 15082705. 
23. ^ Roni Caryn Rabin (2007-08-28). "For a Low-Dose Hormone, Take Your Pick". New York Times. http://query.nytimes.com/gst/fullpage.html?res=9D03E6D91539F93BA1575BC0A9619C8B63&sec=&spon=&pagewanted=1. :Many women seeking natural remedies have turned to compounding pharmacies, druggists who promise so-called bioidentical hormones that are chemically synthesized but have the same molecular structure as hormones produced by a woman's body.
24. ^ Gina Kolata (2007-04-19). "Sharp Drop in Rates of Breast Cancer Holds". New York Times. http://query.nytimes.com/gst/fullpage.html?res=9A03E6D91E3FF93AA25757C0A9619C8B63. 
25. ^ "FDA Takes Action Against Compounded Menopause Hormone Therapy Drugs". FDA. 2008-01-09. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116832.htm. Retrieved 2009-02-17. 
26. ^ Suchowersky O, Muthipeedika J (December 2005). "A case of late-onset chorea". Nat Clin Pract Neurol 1 (2): 113–6. doi:10.1038/ncpneuro0052. PMID 16932507. http://www.nature.com/ncpneuro/journal/v1/n2/full/ncpneuro0052.html. 

External links

• Council on Hormone Education
• North American Menopause Society
• FDA article on Menopause and Hormones
• Effects of hormone replacement